The hallmark of normal aging and of many neurodegenerative diseases is the derangement of the cytoskeleton of the neuron and the deposition of these proteins as filamentous tangles. Research into this manifestation has been slow because human neurofilaments are unique and different from those of laboratory animals. However, many aspects of neurofilament assembly and function are best studied in the neuron -- a largely post- mitotic cell. Thus, ironically, laboratory animals are the experimental systems of choice. Herein we propose to create transgenic mouse lines in which the mouse's neurofilament genes are inactivated and replaced with a set of human neurofilament genes. In Phase I of this process, we will create a stable line of mice in which the genes encoding the three murine subunits have been inactivated by a targeted gene disruption. This mutant line will be examined for neuropathology, reproductive characteristics, or a failure to thrive that might compromise its use as a host for human neurofilament transgenes that will be introduced in Phase II of this application. In Phase II of this application we will produce lines of mice that have been "humanized" with respect to their neurofilament genes and networks using the standard transgenic mouse paradigm. If the project is successful, Taconic Farms will distribute these animals under its exclusive license for knockout rodents. PROPOSED COMMERCIAL APPLICATION The mouse lines that will be created under this grant will be powerful, new research tools for the study of aging and neuro-degenerative diseases, for toxicologic studies of suspected environmental toxins, and the development of new CNS drugs.